L10: Tuberculosis

Tuberculosis (TB) remains one of the world's leading infectious causes of death. Mycobacterium tuberculosis is a slow-growing, obligate aerobic, acid-fast bacillus (AFB) identifiable by the Ziehl-Neelsen (ZN) stain, which relies on the mycobacterial cell wall's high mycolic acid content retaining carbol fuchsin despite acid-alcohol decolorisation. Modern diagnosis uses nucleic acid amplification tests (NAAT, e.g., GeneXpert) that detect M. tuberculosis DNA and concomitant rifampicin resistance within hours.

M. tuberculosis is transmitted by aerosolised droplet nuclei from individuals with active pulmonary TB. Approximately 30% of close contacts of an index case become infected, but only 5–10% of infected immunocompetent individuals develop active disease in their lifetime.

Primary TB describes the initial infection in a previously unexposed individual. After inhalation, bacilli deposit in the lower lobe or mid-zone of the lung (where ventilation is greatest) and are phagocytosed by alveolar macrophages. M. tuberculosis survives intracellularly by inhibiting phagolysosome fusion. In the first 1–3 weeks, bacilli multiply unchecked within macrophages and disseminate via lymphatics to hilar lymph nodes and haematogenously throughout the body (primary bacteraemia), seeding sites including the lung apices, kidneys, meninges, and bone (the preferred sites for secondary TB).

At approximately 3 weeks, a Th1-mediated adaptive immune response is mounted. IFN-γ secreted by CD4+ T cells activates macrophages, enabling them to kill intracellular bacilli and form granulomas. The granuloma consists of activated macrophages transformed into epithelioid cells, which fuse to form Langhans giant cells (nuclei in a horseshoe or peripheral arrangement) surrounded by a cuff of lymphocytes, with central caseous necrosis — a distinctive cheese-like pale, structureless necrosis resulting from a combination of cellular necrosis and immune-mediated killing.

The primary Ghon focus (the parenchymal granuloma) plus the involved hilar lymph node = the Ghon complex (also called the primary complex). In immunocompetent individuals, the Ghon complex heals: the necrotic material calcifies and the granuloma becomes fibrotic, containing viable bacilli in a state of dormancy (latent TB).

Secondary (post-primary) TB occurs in previously sensitised individuals, either from reactivation of latent bacilli or from exogenous reinfection. Because the immune response is now primed, granulomas form rapidly and localise infection — but the inflammatory response also causes significant tissue damage. Secondary TB preferentially affects the lung apices (highest oxygen tension, favoured by obligate aerobes). Cavitary TB is the hallmark: caseous necrosis liquefies and drains into airways, producing a cavity; liquefied caseum is infectious (high bacillary load). Haemoptysis occurs when a vessel is eroded. Widespread bronchogenic spread causes TB pneumonia (military-like within lung). Miliary TB results from haematogenous dissemination: innumerable small (1–2 mm) granulomas resembling millet seeds appear throughout lung, liver, spleen, and other organs — a life-threatening complication.

Interferon-gamma release assays (IGRA, e.g., QuantiFERON-TB Gold) and the Mantoux tuberculin skin test (TST) detect latent TB by measuring T-cell responses to M. tuberculosis antigens; IGRA is not confounded by BCG vaccination. Treatment of active TB uses the RIPE regimen: Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol for 2 months (intensive phase), followed by Rifampicin and Isoniazid for 4 months (continuation phase). Directly observed therapy (DOT) ensures adherence and prevents resistance.